Penicillin compositions for intramuscular injection



April 1956 F. J. KIRCHMEYER ETAL 2,741,573

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PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION 7 Sheets-Sheet 3Filed Dec.

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PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION Filed Dec. 28, 19537 Sheets-Sheet 4 1N9083d 1149/5101 snuv'ua April 10, 1956 F. J.KIRCHMEYER ETAL 2,741,573

PENICILLIN COMPOSITIONS FOR INTRAMUSCULAR INJECTION Filed Dec. 28, 19537 Sheets-Sheet 5 w o w 5 w 3 qmmqh won KEY DYNE -CM Q avsues T5 312,000R Invenzors Frederic/c cLIfir'cbme-ye C. Vincent T5 3 9,000 T 1 4ll,oooT3 1 578,000

7 Sheets-Sheet 6 Inventors Frederick J. Kz'rcbmeyer jfl gk C.(/z'r2ceni' 6 MW (9W fiztorneg 2 3 4 5 6 7' 8 9 TOIFQUf IN w pms-cwApril 10, 1956 F. J. KIRCHMEYER ETAL PENICILLIN COMPOSITIONS FORINTRAMUSCULAR INJECTION Filed Dec. 28, 1953 \V O O O O O 0 O O O m M m ww w. w w w m I. -SQW t QMMQW mom M L W n V645 6 D2:: w BER I Y F m mu mm: uvw

April 10, 1956 PENICILLIN Filed Dec. 28, 3.953

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F. J. KIRCHMEYER ETAL COMPOSITIONS FOR INTRAMUSCULAR INJECTION 7 Sheets-Sheet '7 -ao5 SPEED nv RPM 8 2 3 4 5 6 Y 8 TORQUE //v m DYA/E-CAI =29wwzm United States Patent PENICILLIN COMPOSITIONS FOR INTRA- MUSCULARINJECTION Frederick J. Kirchmeyer, Waukegan, and Hugh C. Vincent, Zion,Ill., assignors to Abbott Laboratories, North Chicago, 111., acorporation of Illinois Application December 28, 1953, Serial No.400,529 Claims. (Cl. 1457-58) This invention relates to new penicillincompositions, and more particularly to an aqueous, injectable penicillincomposition, capable of contributing a new and improved therapeuticeiiect in respect to the duration thereof.

The prior art compositions which have given prolonged therapeuticpenicillin blood levels have been suspensions of penicillin in anon-aqueous menstruum, or in an aqueous menstruum containing a gellingagent, often with a retarding agent to help delay the absorption of thepenicillin into the blood stream. Obviously, non-aqueous menstrua, manyof which have gelling and retarding agents therein, introducedsubstances foreign to the human body and are generally not desirablebecause of possible side reactions, toxicity, sterile abcesses, andother untoward eiiects.

To avoid the foregoing untoward effects, the preferred practice ininjectable penicillin therapy is to avoid as much as possible usingingredients other than penicillin. To achieve the desired highpenicillin blood levels, however, it has heretofore been necessary toinject 2 cc. of the avail.- able aqueous penicillin preparationscontaining about 300,000 units of penicillin per cc. The blood levelsattained therewith, however, are not prolonged for any appreciable time.Thus, with the prior art aqueous penicillin injectable preparations,additional injections must be given every 24 hours or less.

It is therefore a primary object of the present invention to provide anovel aqueous penicillin composition which prolongs the therapeuticallyeffective concentration of penicillin in the blood stream.

It is a further object of the present invention to provide a novelaqueous penicillin composition which maintains an unexpectedly highconcentration of penicillin in the blood stream for a prolonged period.

It is also an object of the present invention to provide a novel aqueouspenicillin composition which maintains an unexpectedly highconcentration of penicillin in the blood stream for an unpredictablyprolonged period without employing non-aqueous menstrua and retardingagents.

It is a still further object of the present invention to provide a novelaqueous penicillin composition which forms a compact depot of arelatively water insoluble penicillin salt upon injectingintramuscularly.

It is also an object of the present invention to provide an improvedaqueous penicillin composition which forms a compact depot when injectedintramuscularly Without presenting objectionable pluggingcharacteristics when injected intramuscularly by means of a standard 20gauge hypodermic needle.

Other objects of the present invention will be apparent from thedetailed description and claims to follow.

It has been discovered that the foregoing and other objects of theinvention are achieved by preparing a penicillin composition comprisingan aqueous suspension of a relatively water insoluble penicillin salt ormixtures of relatively water insoluble penicillin salts which contains aproportion of relatively very finely divided particles of the said saltor salts admixed with a proportion of larger particles of the said saltor salts to form special thixotropic aqueous penicillin suspensioncharacterized by its ability to form a compact depot when injectedintramuscularly through a standard hypodermic needle without giving riseto objectionable resistance or plugging. It has been found that aqueouspenicillin compositions of the above type can be prepared byincorporating a sutiicient proportion or weight per cent of ultra fineparticles of a relatively water insoluble penicillin salt or salts witha proportion of larger particles of a relatively water insolublepenicillin salt or salts in a parenterally acceptable aqueous vehicle.It has been further discovered that the aqueous suspensions ofrelatively water insoluble penicillin salts exhibiting a type ofthixotropy (i. e. the property of becoming or having characteristics ofa fluid when subjected to mechanical disturbance and coagulating orreforming its original structure when the mechanical disturbance isremoved and the materiai allowed to rest) which is characterized byhaving a rheological pattern with a. non-uniform rate of breakdown ofthe original structure with increasing rate of shear are particularlyuseful for providing a compact depot of the said penicillin salt wheninjected into muscular tissue without, however, causing plugging;thereby providing the desired prolonged high therapeutic concentrationof penicillin in the blood stream.

While the thixotropic nature of the compositions of the presentinvention can be detected and measured by a number of devices,particularly reliable and reproducible measurements of the instantthixotropy of an aqueous suspension of relatively water insolublepenicillin salts and particularly of those exhibiting a discontinuous ornonuniform rate of breakdown are obtained with a Hercules high-shearviscometer, an instrument developed by the Hercules Powder Company. (SeeSmith et 211., Paper Trade Jour. 126, 60 (1940).) The commercial form ofthe viscometer is manufactured by the Martinson Machine Company ofKalamazoo, Michigan, and. is the instrument used to make the viscositymeasurements recorded herein and referred to in the several figures ofdrawings.

The Hercules high-shear viscometer continuously records the torque orstress developed on a receiving chamber containing the penicillinsuspension by a rotating bob which is revolved from a zero rate ofrotation of the bob up to the maximum speed of rotation thereof and backto zero speed of rotation. The curve thus obtained which shows the rateof shear plotted against the shearing stress (torque) is called arheogram. The rheological data and curves reported herein were obtainedwith the said Hercules viscometer using Bob B which has a radius of 1.90cm. and a height of 2.50 cm.

The rheogram curve of a fluid (i. e. Newtonian materials) or of aqueouspenicillin suspensions exhibiting properties of a fluid which fail toexhibit the properties of the compositions of the present invention is alinear or substantially linear curve with the upcurve and the downcurveseither exactly coinciding or substantially coinciding (see Figure l forshowing of rheogram curves of aqueous penicillin compositions which failto provide prolonged penicillin blood levels). In contrast with theforegoing, the rheograms of the compositions of the present inventionhave the upcurves displaced laterally from the downcurves so that therheograms define a characteristic loop (see Figure 2 for showing ofrheogram curves of aqueous penicillin compositions which provideprolonged penicillin blood levels). The magnitude of the displacement isrelated to the extent and nature of thixotropic breakdown of thematerial.

A particularly significant and useful feature of the rheograms of thepreferred compositions of the present invention, as will become evidenthereinafter, is the occurrence of a marked change or discontinuity inthe rate WWI-i of structural breakdown of the material being tested at apoint between the zero and maximum value of the ap plied force (R. P.M.), as evidenced by the first marked change in the slope of the upcurveof the rheogram. The maximum torque value expressed in" dyne-centimetersat the instant of the said first marked change in the rate of breakdownof the structure has been arbitrarily designated herein as the T3 of acomposition. It will be evident from the rheograms that the T3 value ispeculiar to those thixotropic materials which exhibit a discontinuous ormarkedly non-uniform rate of breakdown of the initial structure as anincreasing mechanical shearing force is applied. While the precise causeof the non-uniform rate of breakdown of the unique thixotropiccompositions with increasing rate of shear has not been preciselyestablished, it is possible that these compositions have both plasticand dilatant properties superimposed upon basic thixotropiccharacteristics. The T3 values arereadily reproducible with a givenviscometer and are independent of the rate of application of the shearing force, although the T3 absolute values may differ when a differenttype of viscometer is used. It has been found that compositions havingT3 values as determined from rheograms of the Hercules viscometerbetween about 100,000 and 1,000,000 dyne-centimeters, and preferablycompositions having T3 values between about 300,000 and 700,000dyne-centimeters, have the desired attributes of the present inventionand fulfill the objects thereof.

It has been observed that the principal factors which influence therheological pattern and the T3 values of the aqueous penicillin saltcompositions of the present invention wherein the compositions arecomprised of a proportion of very finely divided relatively waterinsoluble penicillin salt or salts admixed with a proportion of largersized particles of a relatively water insoluble penicillin salt or saltsare the specific surface values and the particle size distribution ofthe materials making up the solid phase and, of course, the solids-waterratio used which, however, is largely predetermined by the desired unitconcentration of penicillin per cc. in the final composition. Theparticle size distribution and the specific surface values of the solidcomponents of compositions within the scope of the present invention arebroadly limited by the necessity of the presence of a proportion of veryfinely divided material (i. e. particles between 0 and microns in size)admixed with a proportion of material having an average particle sizesubstantially in excess of the range between 0 and 10 microns andpreferably having an'average length of about 50 microns. Since theparticle size distribution figures and specific surface values areeither very difficult to obtain with a high degree of accuracy or oflittle significance without accurate corollary data, it has accordinglybeen considered particularly advisable and appropriate to define thecompositions of the present invention in terms of their rheograms and T3values which can be shown to, be directly correlated with the physicaland therapeutic in vivo performance of the compositions of the presentinvention.

Particle size distribution studies of the solid components of thecompositions of the present invention, however, are also helpful incharacterizing compositions of the present invention and show that thereis a significant range of distribution of the penicillin salt particles.Thus, in each of the compositions of the instant type which exhibit thedesired physical and therapeutic properties of compositions of thepresent invention, it has been found that the solid component ofthecomposition is comprised.

of particles having a maximum weight per cent in a size ranging between0 and 10 microns in length admixed with particles ranging in lengthbetween about 20 and 100 microns with an average of around 50 microns.Figure 3 contains Several graphs in which the relative weight per centof the penicillin salt particles is plotted against the averagepenicillin salt particle length in microns for a number of aqueouspenicillin compositions embodying the present invention. Figure 4contains several graphs in which the weight per cent is plotted againstthe particle length for a number of aqueous penicillin compositionswhich do not embody the present invention and with which thecompositions embodying the present invention can be compared.

In each of the particle size distribution curves shown in Figure 3illustrating the present invention, it will be evident that a firstmaximum in the distribution curves oc curs within the 0 to 10 micronrange with a less pronounced concentration and wider distribution ofparticles having a size greater than 10 microns in length and betweenabout 20 and microns with an average level of 50 microns or above whichin combination with the particles between 0-10 microns in length providethe aqueous insoluble penicillin salt suspensions of the presentinvention with its improved injectable properties.

Another very significant property which can be used to characterize thecompositions of the present invention and one which greatly influencestherheogram 'of the compositions of the present invention is thespecific surface value of the solid components thereof. For a givensolidswater ratio, it has been found that the specific surface of thedry procaine penicillin powder together with the. particle sizedistribution largely determine the rheological b havior of the saidcompositions. The specific surface values of the solid componentsspecified herein were measured with a precision Blaine air permeabilityfineness tester which is manufactured by the Precision ScientificCompany, Chicago, Illinois (see A. S. T. M. Method C204- 51). i

The Blaine fineness tester consists essentially of a means of drawing adefinite quantity of air through a prepared bed of sample of definiteweight. The number andsize of the pores in this bed are related to thesize of the particles and determines for a given instrument the rate ofair fiow through the bed. The method of preparing the sample andmeasuring the air flow and the equation which is employed to obtain thespecific surface values of the penicillin salt components of the presentinvention are described in A. S. T. M. Method C204- 51. In the saidequation K4 for the specific instrument used in making the measurementsherein, which is designated Model Serial #D-IZ, was determined frommeasurements made at a porosity of 0.500 on National Bureau of StandardsPortland cement sample #114g having an established specific surfacevalue of 3070 square crn./gm. The value of K4 for the said instrumentdetermined under the foregoing conditions is 22.13.

All specific surface measurementsreported herein for the penicillinsamples were evaluated with the Blaine fineness tester Model Serial#D-12 and a modified form of Equation 10 of A. S. T. M. Method C204-51wherein the expression 0.9-10 /e /(0.910e) was employed in place of /e(1e) in an efiort to make the equation less dependent upon porosity wasemployed. Assuming K4 is dependent only upon the instrument used and isindependent of the specific surface of the sample being measured, itsvalue was held at 22.13. The value of p for procaine penicillin employedwas 1.247.

It has been found that the specific surface values of the dry sterilepenicillin salt particles of the present invention which can be used inthe preparation of the aqueous penicillin suspensions of the presentinvention are between about 7,500 and 60,000 square cm./ gm. of thesaidpenicillin salt. For the preferred composition having a unit volumeconcentration of about 550,000 or 600,000 units penicillin per cc. ofsuspension the specific surface value of the dry penicillin saltparticles are between about 14,000 and 35,000 square centimeters pergram.

It should also be understood that the compositions of the presentinvention which have specific surface values within the foregoing rangedo not necessarily have to be comprised of a mixture of two distinct andseparately prepared components having the herein defined averageparticle size distribtuion provided a material having the above surfacevalues can be produced directly by a single grinding operation. Forexample, where an aqueous suspension of a procaine penicillincomposition having a penicillin potency of about 550,000 units per cc.is prepared by having the entire procaine penicillin G componentsthereof subdivided in special laboratory apparatus so as to produce apowder having a specific surface value of 24,000 cm. per gram, improvedblood levels and compact depot formation are exhibited in contrast withthose of compositions having a penicillin concentration of about 550,000units per cc. which do not have specific surface values falling withinthe above specified broad range.

While aqueous penicillin suspensions of the type disclosed herein andhaving the herein disclosed properties can be prepared where thesubdivided relatively insoluble penicillin salt component thereof is theproduct of a single specially controlled grinding operation, it is stillpreferable with the presently available commercial apparatus to preparethe compositions of the present invention by mixing definite proportionsof two relatively water insoluble penicillin salts having relativelydefinite and distinct average particle sizes rather than attempt toobtain the desired particle size distribution by a single carefullycontrolled grinding operation. Thus, whereas it is possible to definethe characteristics of a product made up of predetermined percentages ofparticles within certain size ranges and specific surface values, asherein described, in actual com mercial grinding practice with the typeof grinding apparatus available the specific size grinding and gradingso required is difiicult and inconvenient with ordinary productionapparatus presently available. One difliculty encountered in thisrespect is connected with the particular shape of crystals dealt with,and also the small size of even the largest of them. Crystallineprocaine penicillin upon grinding breaks up into particles having theapproximate shape of an elongated parallelepiped or rod. On this accountthe best criterion to use in an assay of such a mixture is length,rather than volume, and the lengths that have to be dealt with accordingto the invention involve a maximum of about 100 mesh.

One of the features of the present invention, therefore is the discoverythat among the grinding expedients known to the prior art it is possibleby selecting the two different grinding processes known as milling andmicronizing and compounding the natural assortments of relativelyinsoluble penicillin salt particles resulting from those processes inpredetermined ratios in an aqueous medium, it is possible to secure theproper size assortment necessary to secure the unexpected resultsachieved by the present invention.

More specifically, the usual type of high speed hammer mill produces apulverized or miller procaine penicillin which, while varying somewhat,will generally have a particle size distribution approximating thatshown in the following table:

It is readily seen from Table I that the greatest percentage, byrelative weight, of particles are above the 0-10 micron range, andapproximately 50% of the particles fall within the size range of 20-60microns. For convenience, this particular product is called 50 micronssize procaine penicillin, or milled procaine penicillin. The number ofparticles above microns in length are relatively very few but because oftheir much greater weight mistakingly appear as comprising a moresignificant numerical proportion. The specific surface of the sterilizedmilled procaine penicillin G varies between about 4500 to 7000 cm./grm., with a typical lot having a specific surface between about 5600and 6000 crnF/grm.

Similarly a typical finely divided procaine penicillin product which isproduced by a standard high velocity air mill and commonly designated asmicronized has when classified in the following particle size groups aparticle size distribution approximating that shown in Table II:

TABLE II Particle size, Relative weight length in microns percent 0-2 62-4 35 4-6 27 6-10 23 Over 10 9 The greatest percentage by relativeweight of particles shown in Table 11 fall in the range of 2-6 microns,and for convenience the product is called 5 micron size procainepenicillin, or micronized procaine penicillin. The specific surface ofthe micronized procaine penicillin G varies generally between about8,000 and 60,000 cn1. /grrn. with a preferred lot having a specificsurface of about 31,000 cm. /grm.

It has been found that, for the preferred embodiment of this invention,a satisfactory 50 micron size grind or milled material is one thatcontains at least 50% by relative weight of particles in the 20-60micron particle size range. The milled product should not have a greatmany particles substantially longer than about 100 microns in size.Similarly, the 5 micron grind or micronized material preferably has asubstantial proportion of the particles less than 10 microns in lengthalthough this is not an important limitation provided the specificsurface of the micronized relatively insoluble salt is within the broadrange disclosed herein. The micronized product has been foundsatisfactory where at least 60% by relative weight is in the particlesize range of less than 6 microns in length.

As a further embodiment of the present invention, milled and micronizedprocaine penicillin having the particle size distribution shown infollowing Table III and Table IV have been used with marked success:

It is readily seen from Table III that the greatest percentage, byrelative weight, of particles are over 30 microns, and at leastapproximately 50% of the particles fall within the size range of 30-70microns. For convenience, this particular product is called 50 micronsize procaine penicillin, or milled procaine penicillin. Ideally, themilled product should have no particles greater than 100 microns insize.

, 7 "IABLlEiIV "Micronized procaine penicillin 'Particle size, length inmicrons Relative Weight percent The greatest percentage, by relativeweight, of particles shown'in Table IV fall in the range of 2-6 micronsand for convenience the product is called micron size procainepenicillin, or micronized procaine penicillin. Ideally, the micronizedsalt should have no particles greater than lOmicrons.

Specifically, the present invention is illustrated in detail in thefollowing examples but it should be understood that the examples areonly by way of illustration and the invention is not intended to belimited to the specific components disclosed nor to the preciseproportions employe'd'therein.

EXA MPLE 1 Materials for 1000 cc. of suspension containing 600,000 unitsprocaine penicillinper cc.:

Penicillin G procaine, crystalline, milled, 985

u./mg. (specific surface=5,600 cm. /gm.) gm 304.6

Penicillin G procaine, crystalline, mieronized, 985

u./mg (specific'surface=24,100 cmfi/gm.) gm 304.6

Sodium citrate grn 14.0 Wetting agent, Tween 80 "gm 1.0 Methyl Parabengm 0.943 Propyl Paraben gm 0.105 Water, pure for injection cc 524.0

of'0.0l to 1.0%, however, 0.1% by weight of the wetting agent providesan elegant suspension without excessive amounts of the wetting agent.

A bacteriostatic may be employed as an added precaution to supply asterile'product. In Example I the Methyl Paraben and Propyl Paraben areadded as bacteriostatics. (Methyl Paraben is methylpara-hydroxybenzoate, and likewise Propyl Paraben is propylpara-hydroxybenzoate).

The procaine penicillin salt particles of the aqueous suspensionprepared in the above manner have a specific surface value of 14,850square centimeters per gram and the suspension exhibits the rheogramshown in curve R of Figure 5 and an average T3 value of 309,000dynecentimeters. The particle size distribution curve of the penicillinsalt components of the above aqueous suspension has one maximum at 7.5microns and a second lessor maximum at 67 microns with the relativeweight percent of the particles at the said peaks being 18 and 7 percentrespectively (see curve vK, Figure 3). The above aqueous suspension isreadily injected without objectionable plugging into muscle tissue orinto a 2% aqueous gelatin gel forming a compact spherical depot and wheninjected into humans provides a high therapeutic penicillin blood levelsubstantially in excess of 48 hours.

EXAMPLE l 11 Following the procedure of Example I, a suspensioncontaining 600,000 units of penicillin per cc. is produced havingingredients according to the following table:

Materials for 1000 cc. of suspension containing 600,000 units procainepenicillin per cc.:

The aqueous suspension is filled into 1 cc. sterile Penicillin Gprocaine, crystalline, milled, 9 85 p u.'/mg g"rn -152:3 Penicillin Gpr'oc'ain'e, crystalline, micronized,98'5

tn/mg gm 4569 Sodium citrate "gm "1410 Tween gm 1.0- Methyl Paraben 'gm0.943- Propyl parab'en gm 0.105 Water for injection cc 524.0-

The aqueous suspension thus formed is readily-injected. in tramuscularly through a standard 20-gaugehypodermie needle and-maintains-atherapeutic penicillinblood levell fora prolonged period.

EXAMPLE in Materials for a suspen'si'onc'ontaining 700,000 units of.'

procaine penicillin percc. areas follows:

Penicillin G procaine, crystalline, milled, 985

u./mg gm 8391' Penicillin G procaine, crystalline, micronized, 985

u./mg -gm 2.797 Tween 80 -gm 0.0157 Distilled water cc 7.0

The procaine penicillin mixture prepared by thoroughly premixing the twodificrent procaine penicillin ground products is admixed with the waterhaving the Tween 80 dissolved therein. The'suspen'sion is thoroughlymixed and filled into 1 cc.-ampoules as in Example I.

The-aqueous suspension thus formed is readily injected intramuscularlythrough a standard ZO-g'au'ge hypodermic needle and maintains atherapeuticpenicillin blood level for a prolongedperiod.

EXAMPLE IV Materials-for 1000 cc. of suspension containing 552,000 unitsprocaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

The above ingredients are combined precisely as described in Example Ito provide 1000 cc. of an aqueous procaine penicillin G suspensioncontaining 552,000 units of penicillin per cc.

The aqueous penicillin suspension prepared in the above manner exhibitsthe rheogram shown in curve Q ofFigure 5 and an averageT value of312,000 dyne-centimeters. The specific surface of the dry finely dividedsterile procaine penicillin G powder mixture is 15,620 squarecentimeters per gram. The said penicillin suspension' is readilyinjectable into muscle tissue through a standard ZO-gauge hypodermicneedle and forms a com pact spherical depot characteristic of thepreferred compositions of the present invention and produces prolongedtherapeutic blood levels in excess of 48 hours.

EXAMPLE V Materials for 1000 cc. of suspension containing 552,000 unitsprocaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

9 V The foregoing ingredients are combined in accordance with theprocedure described in Example I to provide an aqueous penicillin Gsuspension having a concentration of 552,000 units penicillin per cc.The said suspension exhibits a rheogram as shown by curve S of Figureand an average T3 value of 411,000 dyne-centimeters. The sterilizedfinely divided procaine penicillin G has a specific surface of 20,200square centimeters per gram. Upon injecting into muscle tissue through astandard 20-gauge hypodermic needle the said suspension forms a compactspherical depot which exhibits an unexpectedly prolonged and high bloodlevel as will be shown by subsequent data (Table V).

EXAMPLE VI Materials for 1000 cc. of suspension containing 552,000 unitsprocaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm..- 139.4 Penicillin Gprocaine, crystalline, micronized, 990

Following the procedure for Example I, the foregoing ingredients arecombined to provide an aqueous suspension of procaine penicillin Gcontaining 552,000 units of penicillin per cc.

The penicillin suspension prepared in the above manner exhibits therheogram shown by curve T of Figure 5 of the drawing and an average Tsvalue of 578,000 dynecentimeters. The finely divided procaine penicillinG powder after sterilization has a specific surface of 24,000 squarecentimeters per gram and has 23% by weight of the particles Within therange of 05 microns. The particle size distribution curve of the finelydivided material of the aqueous suspension exhibits one maximum at 7.5microns and a second maximum at 55 microns, with a relative weight percent of 40 and 2 respectively at the foregoing maximums (see curve I ofFigure 3). Upon injection into muscle tissue through a standard ZO-gaugehypodermic needle the foregoing aqueous penicillin suspension forms acompact spherical depot which maintains a remarkably high penicillinblood level for a prolonged period (see Table V).

EXAMPLE VII Materials for 1000 cc. of suspension containing 552,000units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm 139.4 Penicillin G procaine,crystalline, micronized, 990

u./mg. (specific surface=33,700 cmF/gm.) gm 418.2 Sodium citrate gm 15.0Tween 80, wetting agent gm 1.10 Methyl Paraben gm 1.00 Propyl Paraben gm.112 Water, pure for injection cc 545.4

EXAMPLE VIII Materials for 1000 cc. of suspension containing 450,000units procaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990

u./mg. (specific surface=6,000 cm. /gm.) gm 113.6

Penicillin G procaine, crystalline, micronized, 990

u./mg. (specific surface=31,300 cm. gm.) gm 340.9

The solid penicillin ingredients having a specific surface of 24,000 cm./gm. are combined in accordance with the procedure described in ExampleI to provide an aqueous penicillin G suspension having a concentrationof 450,000 units penicillin per cc. The foregoing aqueous suspensionexhibits a rheogram as shown in curve Y of Figure 7 and an average Tavalue of 132,000 dyne-centimeters. Upon injecting into muscle tissue ora 2% aqueous gelatin gel a generally oval shaped depot is formed. Thesaid suspension when injected into humans provides improved blood levelvalues over aqueous penicillin suspensions of equal potency which do notemploy the present invention.

EXAMPLE IX Materials for 1000 cc. of suspension containing 552,000 unitsof procaine penicillin per cc.:

Sterile penicillin G procaine, coarse micronized, 990

u./mg. (specific surface=19,l00 cm. /grn.) gm 557.6

The above ingredients are combined precisely as described in Example Ito provide 1000 cc. of an aqueous procaine penicillin G suspensioncontaining 552,000 units of penicillin per cc.

The aqueous penicillin suspension prepared in the above manner exhibitsa rheogram as shown by curve W of Figure 6 and an average T3 value of572,000 dyne-centimeters. The specific surface of the dry sterilizedfinelydivided procaine penicillin G in the above suspension is 19,100square centimeters per gram. The said procaine penicillin G has 27% byweight of particles within the range of 0-5 microns. The particle sizedistribution curve of the said aqueous suspension has a maximum at 7.5microns with a secondary maximum or plateau at about 70 microns with arelative weight per cent of 45 at the 7.5 micron maximum. Upon injectingthe said aqueous suspension through a standard ZO-gauge hypodermicneedle into muscle tissue or into 2% aqueous gelatin gel a compactspherical depot is formed and clinical data show that unexpectedlyprolonged and high penicillin blood levels are produced by the saidsuspension.

EXAMPLE X Materials for 1000 cc. of suspension containing 552,000 unitsprocaine penicillin per cc.:

Penicillin G procaine, crystalline, milled, 990 u./

mg. (specific surface=6,330 cm. /gm..) gm 223.0 Penicillin G procaine,crystalline, micronized,

The above ingredients are combined precisely as described in ExampleI'to provide 1000 cc. of an aqueous pi'o'caine-penicillinsttspensien-enntaiein 5 2,000 units of penicillin per cc.

The above aqueousgsuspension exhibits arheogram'as shown by curve V ofFigure 6 and an average-T3 value of 414,000 dyne-cntimeters. The drysterile finely divided procaine penicillin G of the abovesuspension-immediately prior to admixing with the aqueous vehicle has aspecific surface of 25,000 square centimeters 'per'gram. The

said suspension is readily injected through a standard 20- gaugehypodermic needle and form a compact spherical depot when injectingintolnuscleitissue era 2% aqueous gelatin gel. Substantiallyimproved andprolongedpenicillin blood levels are "produced by thesaidcompositionwhen injected intramuscula1'ly"into humans.

EXAMPLE XI *M'at'erials for 1000"cc. of suspension containing 552,000units procainepenicillin Gpercc; Penicillin G procaine, crystalline,milled, 990 u./

mg. (specific surface= 5,660 .cm. /gm.) gm 139.4 Penicillin G procaine,crystalline, rnicronized,

gm.) gm- 418.2 S odium cit rate gm 14.0 Wetting agent, Tween 80 gm 1.00Methyl Paraben gm 1.00 Propyl Paraben 'gm 0.100 Water, pure forinjection cc.. 545.4

The above ingredients are combindpreciselyas described in Example I toprovide 1000 cc. of an aqueous procaine penicillin G suspensioncontaining 552,000 units of penicillin per cc.

The above. aqueous. penicillin suspension exhibits =a rheogram asshownin curveXof Figure 7"-and' an average T3 of 102,000 (tyne-centimeters.

EXAMPLE XII Material for 1000 cc.of aqueous suspension containing400,000 units N-methyl-l,2 diphenyl-2-hydroxyethylamine penicillin Gsalt per cc.: N-methyH,2 diphenyl-2-hydroxyethylamine penicillin G salt,microcrystalline mixture grn 350 Sodium citrate gm 18.80 Wetting agent,Tween 80 gm 1.17 MethylParab'en gm 1.26 Propyl Paraben -gm .14 Water,pure for injection cc 720 The above ingredients, otherthan thepenicillinsalt, are dissolved in water and thereafter the aqueoussolution is slowly added to the powdered penicillin salt with thoroughstirring to provide an aqueous penicillin suspension containing400,000'units of penicillin per cc.

The above aqueous penicillin suspension exhibits a rheogram as shown bycurve H of Figure 2 and has a T3 value of 1,015,000 dyne-centimeters.The dry sterile penicillin salt powder has a specific surface value of 35,000 cm. gm. and has a maximum weight per centparticle distributionpeak below 5 microns. through a standard 20-gauge hypodermic needle into-muscle tissue and into-a 2% aqueous gelatin gel acornpact sphericaldepot is formed.

EXAMPLE XIII Material-for 1000ccl of aqueous suspension containing500,000 units N,N-dibenzylethylenediamine penicillin G salt per cc.:

N;N-dibenzylethylenediamine penicillin G salt, I

microcrystalline mixture gm 476 Sodium citrate gm -16.0 'Wetting agent,Tween 80 gm- 1.0 I Methyl Paraben 1 gm 1.08 Propyl Paraben gm 0.12Water, pure 1501' ll'1j0tl()fl.;:; 4;...' ..:LQCC 598 Upon injectingdepot is formed.

EXAMPLE XIV Materials for 1000 cc. ofaqueous suspension 'containing400,000 units procaine penicillin G per 00.:

Penicillin G. procaine, milled, 990 u./n1g. (specific surface='5,700 Cru/gm.) gm 101.0 Penicillin G procaine, micronized, 990 u./rng. specificsurface=63,700 sq. cm./gin.) gm 303.0 Sodium citrate gm 18.8 "Tween80,"wetting agent gm 1.17 Methyl Par'aben gm 1.26 'PropylPar aben gm .14Water, pure for injection cc 666.7

The'above ingredients, other than 'the'penicillin salt, arei'dissolvedun' the water and thereafter the aqueous solution is slowly added tothe powdered penicillin salt with thorough stirring to provide anaqueousp'enicillin suspension containing 400,000 units of penicillin percc. The above aqueous penicillin suspension exhibits a Tav'alue of490,000 dyne-centimeters. The penicillin salt componenthasaspecificsurfacevalue of 49,200 cm. gm. and has" amaximum weight percent particle distribution 'peak below 5 'microns. T he aqueoussuspension is readily 'irijectable through a standard ZO-gaugehypodermic needle to form a compact sphericaldepot in muscle tissue.

EXAMPLE XV Materials for aqueous suspension containing 700,000 units ofprocaine penicillin G per 00.:

' Penicillin G procaine, n1illed, 990 u./rng. (specific I surface: 5,700cm. /gm.) h gm 184.5

Penicillin G procaine, micromilled, 990 u./mg.

(specific surface=10,000 cm. /gm.) g1n 61.5 Sodium citrate gm 4.04 Tween80, wetting agent gm 0.25 Methyl Paraben -gm 0.27 "Propyl Paraben gm0.16 Water, pure for injection cc 148.4

' The above ingredients, other than the penicillin sa1t,'arcdissolved'inthe water and thereaiterthe aqueous solution is slowly addedto the powdered penicillin salt wi'ththorbugh stirring to provide anaqueous penicillin suspension containing 400,000 units of penicillin percc.

The above aqueous penicillin suspension exhibits acharacteri'sticrheo'gram with a T3 value of 275,000 dyne-centimeters.

EXAMPLE XVI Material for 1000 cc. of aqueoussuspens'ion containing750000 units procaine penicillin G per cc.:

PenicillinG procaine, milled, 99 u./mg. (specific "'surface'=5;700 cm./gm.) "gm" 568.2

' Penicillin G procaine, micromilled, 990 u./mg.

(specific -surf'ace=10,000 cmfl/gm.) gm 189.4 Sodium-citrate.- grn 10.72Twe'enj 80, wetti ng agent gm .666 "Methyl'Parabena grn ".716 PropylParaben; gm -079 Water, pure for injection 'cc 386.4

The above ingredients, other than the penicillin salt, are dissolved inthe water and thereafter the aqueous solution is slowly added to thepowdered penicillin salt with thorough stirring to provide anaqueouspenicillin suspension containing 400,000 units of penicillin per cc.

The above aqueous penicillin suspension exhibits a characteristicrheogram with a T3 value of 900,000 dynecentimeters.

EXAMPLE XVII Material for 1000 cc. of aqueous suspension containingabout 550,000 units penicillin per 00.:

Pencillin G procaine, milled, 990 u./mg. (specific surface=5,700cmP/gm.) gm- 138.9 N,N-bis-dehydroabietylethylenediamine dipenicillin Gsalt, 939 u./mg gm 458.3 Sodium citrate gm 15.0 Tween 80, wetting agentgm .928 Methyl Paraben gm 1.00 Propyl Paraben gm 0.112 Water, pure forinjection cc 482.6

The above ingredients, other than the penicillin salt, are dissolved inthe Water and thereafter the aqueous solution is slowly added to thepowdered pencillin salt with thorough stirring to provide an aqueouspenicillin suspension containing 550,000 units of penicillin per cc.

The above aqueous penicillin suspension is readily injected through astandard ZO-gauge hypodermic needle and forms a compact spherical depotwhen injected into muscle tissue.

TABLE V Summary of penicillin blood level medians, penicillin units percc. blood at indicated hours after injection Aqueous Suspension 4 24 4872 96 Pro u hours hours hours hours hours Example V 2. 5 1. 25 0. 624Example VI. 10.0 2. 5 0. 624 Example VIL. 7. 5 2. 5 0. 624 ExampleVIII... 0.936 0. 624 0.312 Example IX. 1.25 O. 468 0. 624 Example X 0.936 O. 468 0. 312 Example XI. 0. 312 0. 312 0.156

Median Values 1. 25 0. 624 0. 624

The data of Table V summarizing the clinical blood level studies wereobtanied from clinical use of the indicated aqueous penicillinsuspensions in humans under actual therapeutic use conditions. It willbe evident from Table V and the specific examples to which reference ismade that the preferred suspensions of the present invention having a T3value between 300,000 and 700,000 dynecentimeters maintains hightherapeutic penicillin blood levels for a period of at least 72 hoursafter intramuscular injection and all of the aqueous suspensions havinga T3 value above 100,000 dyne-centimeters maintains a penicillin bloodlevel substantially in excess of the minimum therapeutic blood level of.03 unit penicillin per cc. for at least 72 hours.

The data of Table V also makes it possible to correlate the severalphysical characteristics of the aqueous penicillin suspensions of thepresent invention with the ability of the suspensions to maintainpenicillin blood levels in humans. Accordingly, it has been observedthat the readaccordance with the foregoing disclosure maintains aprolonged therapeutic blood level out of all proportion to the increaseddosage and also permits administration intramuscularly through astandard hypodermic needle without objectionable plugging. It isbelieved that the great increase in therapeutic effectiveness andimproved injectable properties is contingent on or correlated with theassortment of particle sizes of the relatively water insoluble orsparingly soluble penicillin salt employed which appears to greatlyincrease the original penicillin concentration of the depot formed uponinjecting the suspensions intramuscularly, while at the same timepermitting the high potency, compact depot forming, aqueous penicillinsuspensions being readily injectable into muscle tissue through astandard ZO-gauge hypodermic needle.

The particle size distribution data disclosed in the foregoingdescription and specified in the claims were obtained by suspending thefinely divided penicillin salt in an aqueous menstruum of substantiallythe same composition as the vehicle used in the specific examples toprepare the injectable suspension and examining a sealed representativesample thereof first under a Bausch and Lomb Model LC-4 polarizingmicroscope with Nicol prisms removed, the image of which is preferablythrown upon the ground glass screen of a Bausch and Lomb Model Lphotomicrographic camera, and the particles counted in increment groupsof 10 microns down to the 20-30 micron group while using a totalmagnification of 200 diameters. Thereafter photomicrographs are takenwith the said apparatus using a total magnification of 1000 diametersand the final three divisions, namely the 10-20 micron group, the 5 to10 micron group, and the 0.01 to 5 micron groups, are counted. Theaverage Weight per cent values are calculated in the usual manner fromthe foregoing numerical count after determining the average length andwidth of the particles in each increment group, except the two smallestgroups for which the length to width ratio is assumed to approach unityexponentially as the particle size approaches zero and the furtherempirical assumption that the depth to width ratio is the same as thewidth to length ratio, an assumption which was found to conform with theactual measurements made. The term relative weight is an approximationof the proportionate weight of various size groupings, and is based uponthe microscopically measured size and number of crystals multiplied togive their volume, which is in turn proportional to the weight since allcrystals of a given penicillin salt are assumed to have the samedensity.

While procaine penicillin has been used most extensively to illustratethe present invention, in the instant description and claims the termrelatively water insoluble penicillin salt designates anytherapeutically useful penicillin salt having a water solubility equalto procaine penicillin and also those having a water solubility lessthan procaine penicillin which is approximately 7000 units penicillinper cc. Among the class of sparingly soluble penicillin salts hereindesignated as relatively water insoluble penicillin salts in addition toprocaine penicillin are N-methyl- 1,2-diphenyl-2-hydroxyethylaminepenicillin salt, N,N- dibenzylethylenediamine penicillin salt, andN,N-bisdehydroabietylethylenediarnine penicillin salt and othersparingly soluble rosin amine penicillin salts. It should be understoodthat the improved compositions of the present invention can be preparedby forming an aqueous suspension of any one of the relatively waterinsoluble penicillin salts of the above type in the specified finelydivided state or by suspending a mixture of two or more of the saidrelatively water insoluble penicillin salts in the specified finelydivided state. When the composition is prepared entirely from a waterinsoluble penicillin salt, such as N,N-dibenzylethylenediaminepenicillin G salt, penicillin is detectable in the blood for severalmonths after being injected intramuscularly. In some instances, however,it is preferable to combine procaine penicillin 15 with a lesssoluble'penicillin salt, suchas N,N'. dibenzyl- "ethylened'iaminepenicillin G salt, according to the manner specifiedherein in.anydesiredproportion and thereby obtain a therapeutic bood level for a periodsubstantially longer-than is possible when procaine penicillin. alone isused.

Theterm high potency as used herein and in the claimsdesignates apenicillin. composition having a unit concentration in excess of a'unit' volume concentration of 300,000 units per cc. and having at least400,000 units penicillin'per cc. In the preferred embodiment of theinvention the compositions have a unit concentration of at leastab'out500,000 and preferably between 550,000'and "750,000units penicillin'per'cc. it should be apparent from the specific examples, however, that bychoosing and ,proportioning a"penicillinsaltor' mixture of penicillin"saltsof'thespecified'type having the properparticle size distributionandspecificsurface, itis possible to prepare "an aqueous penicillinsuspensionhaving a unit concentration'Within the above'specified limitswhich has a'T value suflic'ient' toprovide the composition with thedesirable characteristics specified herein.

The specific embodiments of'the invention disclosed hereinhave employeda parenterally acceptable aqueous vehicle'which has been madeapproximately. isotonic by the addition of sodium citrate so as tominimize the degreeof pain incident with intramuscular injections. How-'"ever, any physiologically compatible isotonic solution, such as asodium chloride solution or even puredistilled'water may be used for thesuspension. The use of any parenteral'ly acceptable wetting agent,'suchas Tween 80, facilitates -"the'preparation of the suspension and the useof preservatives, such as Methyl and Propyl'Paraben; are desirable whereit'is intended 'to'store the'preparation prior to administration.

This application is a 'continuation-in-part application of applicantsco-pending application, Serial No. 134,138,

filed December 20, 1949, and now abandoned.

' Others'may readily adapt theinvention for'use under various conditionsof service by employing one or more of the novel features disclosed orequivalents thereof. As presently advised with respect to the apparentscope "of our invention, we desire to claim the following subject'"matter.

1. A high potency aqueous penicillin composition comprising a suspensionof at leastone finely divided relatively-water insoluble penicillin saltin an aqueous vehicle suitable for intramuscular injection, and having aunit volume concentration between 400,000 and about 750,000

units penicillin per cc., said suspension containing a proportion ofrelatively very finely divided particles of the "relatively waterinsoluble penicillin saltadmixed with a proportion of relatively largerparticles of the finely divided relatively water insoluble penicillinsalt, the mixture of the finely divided relatively water insolublepenicillin "salt particles having a particle size distribution curvewith one maximum thereof occurring between the to micron particle sizerange and a second maximum occurring above about the 50 micronparticlesize range, and said suspension forming a thixotropic aqueoussuspension "having a rheogram curve which exhibits a T3 value betweenabout l00,000 and 1,000,000 dyne-centimeters.

2. A high potency aqueous penicillin composition comprising aninjectable suspension of a relatively water insoluble penicillin saltdispersed in an aqueous menstruum suitable for intramuscular injection,and having a unit volume concentration in excess of about 400,000 unitsper cc, said insoluble penicillin salt consisting of particles of afinely clivided'relatively Water insoluble penicillin salt having themajor weight fraction thereof with a par- "ticle size between 0 and 10microns and havingthe said particles between O and 10"micro'ns'adrnixedwith-par- ""-ticl'e'sof finely *divided relatively water insolublepenicillin "16 salt having an average. particle size' of" about microns,said suspension, forming a thixotropic aqueous suspension having arheogramcurve which exhibits aTs value between about l00,000 and1,000,000 *dyne-centimeters.

3. A high potency aqueous penicillin composition'substantially asdescribed in claim 2 wherein the-relatively water insoluble penicillinsalt is procaine penicillin.

4. A high potency aqueous penicillin composition substantially asdescribed in claim 2 wherein the relatively water insoluble penicillinsalt is' an N,N'"-b,is-dehydrcabiethylethylenediamine penicillin salt.

5. Ahigh potency aqueous penicillin composition sub stantially asdescribed in claim 2 whereinlthe particles of the relatively waterinsolublepenicillin salt above 10 microns in size have an averageparticlesize between 30 and microns.

6. A high potency aqueous penicillin composition substantially asdescribed in claim 2 wherein the said weight fraction incrementofparticles of the insoluble. penicillin salt between 0' and 10 micronsis greater'than the sum of the 10 micron weight fraction increments ofthe said particles above 10 micronsin length.

prising an'injectable suspension of a relatively water insolublepenicillin salt dispersed in anaqueous menstruum suitablefor-intramuscular injection and having a unit volume concentration inexcess of about 400,000 units per cc., said insoluble penicillin saltconsisting offinely divided particles of a relatively water insolublepenicillin saltihaving the major weight fraction thereof with a particlelength between 0 and 10 microns and'having the said particles of thepenicillin salt above 10 microns in length of an average particle lengthbetween about 30, and 70 microns, and said suspension forming athixotropic aqueous suspension having a 'rheogram curve which exhibits aT3 value between about 100,000 and l,000',000 dyne-centimeters.

8. A high potency aqueous penicillin composition substantially asdescribed in claim 7 wherein the: relatively water insoluble penicillinsalt has a specific surface'between about 7,500 and 60,000 squarecentimeters per gram.

'9. A high potency injectableaqueous penicillin composition comprising afinely divided relatively water-insoluble penicillin salt suspended in aparenterally acceptable aqueous'vehicle and having a unit concentrationof at least 400,000 units penicillin per cc., said penicillin saltconsisting of between about 25 to of the said penicillin salt of about 5micron average particle. size and the remainder of the said penicillin.salt being of about 50 micron average particle size.

10. A high potency injectable. aqueous penicillin composition comprisinga finely divided relatively waterinsoluble penicillin salt suspended ina parenterally acceptable aqueous vehicle and having a unitconcentration of at least 400,000 units penicillin per cc., saidpenicillin salt consisting of between about 25 to 75 procaine penicillin.of about 5 micron average particle size and'the remainder of theprocaine penicillin being of about 50 micron average particle size.

11. A high potency injectable aqueous procaine penicillin compositioncomprising a finelydivided relatively water insoluble procainepenicillin salt suspended in a parenterally acceptable aqueous vehicleand having a,-unit concentration of at least 400,000 units procainepenicillin per cc., said penicillin salt consisting of about 75%-of thesaid penicillin salt of about 5 micron average particlesize and theremainder of the said penicillin salt being of about 50 micron averageparticle size, and a small percentage of an innocuous wetting agent.

12. A high potency aqueous injectable procaine penicillin G compositioncontaining atleast 400,000 units of penicillin per cc., which consistsof 25 to 75 of procaine penicillin having an average particle'size ofsubstantially 5 microns, the remainderof the procaine penicillin having17 an average particle size of substantially 50 microns, and a smallpercentage of an innocuous wetting agent.

13. A high potency aqueous injectable procaine penicillin G compositioncontaining between about 400,000 and 750,000 units of penicillin percc., which consists of at least about 25% of procaine penicillin Gparticles hav-- ing up to about a micron average particle size, at leastabout 25% of particles of the procaine penicillin of about 50 micronaverage size, and a small percentage of an innocuous Wetting agent.

14. An injectable penicillin composition having a potency of at least400,000 units of penicillin per cc., consisting of 25-75% ofprocaine-penicillin particles having an average particle size of about 5microns, the remainder of the procaine penicillin particles having anaverage size of about 50 microns, said procaine penicillin mixture beingsuspended in an aqueous isotonic solution containing a small amount ofan innocuous wetting agent.

15. An injectable penicillin composition having a potency of at least400,000 units of penicillin per cc., comprising about 50% of procainepenicillin particles having an average size of about 5 microns, theremainder of the procaine penicillin particles having an average size ofabout 50 microns, said procaine penicillin mixture being suspended in anaqueous isotonic sodium citrate solution containing a small amount of awetting agent.

16. An injectable penicillin composition having a potency of at least400,000 units of penicillin per cc., consisting of a mixture of milledand micronized procaine penicillin in aqueous suspension, the micronizedprocaine penicillin being about one-tenth as large as the milledprocaine penicillin and constituting about 2575% of the mixture.

17. An injectable penicillin composition having a potency of at leastabout 400,000 units of penicillin per cc., comprising a mixture ofprocaine penicillin particles having 80% of an average length of about 5microns and the remainder of the procaine penicillin particles having anaverage length of about microns, said procaine penicillin mixture beingsuspended in an aqueous solution containing a small amount of a wettingagent.

18. An injectable aqueous penicillin composition having a potency of atleast 400,000 units of penicillin per cc., comprising suspensioncontaining more than 45% by weight of suspended procaine penicillin,said penicillin consisting of 25-75% micronized procaine penicillin andthe remainder milled procaine penicillin.

19. An injectable aqueous penicillin composition hava potency of atleast 400,000 units of penicillin per cc., comprising suspensioncontaining about by weight of suspended procaine penicillin, saidpenicillin consisting of 25-75% micronized procaine penicillin and theremainder milled procaine penicillin.

20. An injectable aqueous high potency penicillin composition comprisinga substantial proportion of a relatively water insoluble penicillin saltsuspended in an aqueous vehicle suitable for intramuscular injectionhaving a unit volume concentration of between about 500,000 and 700,000units per cc., said penicillin salt comprising about micronizedpenicillin salt. and the balance of the said penicillin salt beingmilled penicillin salt.

References Cited in the file of this patent UNITED STATES PATENTS YoungJuly 14, 1953

1. A HIGH POTENCY AQUEOUS PENICILLIN COMPOSITION COMPRISING A SUSPENSIONOF AT LEAST ONE FINELY DIVIDED RELATIVELY WATER INSOLUBLE PENCILLIN SALTIN AN AQUEOUS VEHICLE SUITABLE FOR INTRAMUSCULAR INJECTION, AND HAVING AUNIT VOLUME CONCENTRATION BETWEEN 400,000 AND ABOUT 750,000 UNITSPENCILLIN PER CC., SAID SUSPENSION CONTAINING A PROPORTION OFRELVATIVELY VERY FINELY DIVIDED PARTICLES OF THE RELATIVELY WATERINSOLUBLE PENCILLIN SALT ADMIXED WITH A RELATIVELY WATER INSOLUBLEPENCILLIN SALT, THE MIXTURE OF THE FINELY DIVIDED RELATIVELY WATERINSOLUBLE PENCILLIN SALT PARTICLES HAVING A PARTICLE SIZE DISTRIBUTIONCURVE WITH ONE MAXIMUM THEREOF OCCURRING BETWEEN THE 0 TO 10 MICRONPARTICLE SIZE RANGE AND A SECOND MAXIMUM OCCURRING ABOVE ABOUT THE 50MICRON PARTICLES SIZE RANGE, AND SAID SUSPENSION FORMING A THIXOTROPICAQUEOUS SUSPENSION HAVING A RHEOGRAM CURVE WHICH EXHIBITS A T3 VALUEBETWEEN ABOUT 10,000 AND 1,000,000 DYNE-CENTIMETERS.